Mechanism of HIF-1α-dependent suppression of hypoxia-induced apoptosis in squamous cell carcinoma cells
Mechanism of HIF-1α-dependent suppression of hypoxia-induced apoptosis in squamous cell carcinoma cells
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DOI：
10.1111/j.1349-7006.2005.00065.x
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发表时间：
2005-07-01
期刊：
影响因子：
5.7
通讯作者：
Osaki, T
中科院分区：
文献类型：
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作者：
Sasabe, E;Tatemoto, Y;Osaki, T
缺氧诱导因子-1（hypoxia-inducible factor-1，HIF-1）在实体瘤细胞的生长和存活中起重要作用。HIF-1 α的过表达已在许多人类肿瘤中得到证实，并预示着对放化疗的不良反应。我们研究了HIF-1 α诱导的人口腔鳞状细胞癌细胞（OSCC）系的生存途径。结果表明，HIF-1a的强制表达通过抑制线粒体细胞色素c的释放来抑制缺氧诱导的OSCC细胞凋亡。HIF-1a过表达可抑制细胞内活性氧（ROS）的产生、细胞内Ca 2+浓度的升高、线粒体膜电位的降低和细胞色素c在胞浆中的积聚，从而导致caspase-9和caspase-3的失活。此外，在HIF-1 α过表达的OSCC细胞系中，抗凋亡Bcl-2和BCl-X-L水平升高，促凋亡Bax和巴克水平降低。HIF-1 α的过表达也增加了Akt和细胞外信号调节激酶（ERK）的磷酸化水平。这些发现表明HIF-1a通过两种机制防止凋亡性细胞死亡，包括抑制细胞色素c释放和激活Akt和ERK。
The transcriptional factor hypoxia-inducible factor-1 (HIF-1) plays an important role in solid tumor cell growth and survival. Overexpression of HIF-1 alpha has been demonstrated in many human tumors and predicts a poor response to chemoradiotherapy. We examined the HIF-1 alpha-induced survival pathways in human oral squamous cell carcinoma cell (OSCC) lines. The results showed that forced expression of HIF-1a suppressed hypoxia-induced apoptosis of OSCC lines by inhibiting cytochrome c release from mitochondria. Overexpression of HIF-1a inhibited the generation of reactive oxygen species (ROS), elevation of intracellular Ca2+ concentration, reduction of mitochondrial membrane potential, and cytosolic accumulation of cytochrome c, which resulted in the inactivation of caspase-9 and caspase-3. In addition, antiapoptotic BcI-2 and BCl-X-L levels were increased and pro-apoptotic Bax and Bak levels were decreased in the HIF-1 alpha-overexpressing OSCC line. Overexpression of HIF-1 alpha also increased the levels of phosphorylation of Akt and extracellular signal-regulated kinases (ERK). These findings indicate that HIF-1a prevents apoptotic cell death through two mechanisms, including inhibition of cytochrome c release and activation of Akt and ERK.